A status of immunological hyper-reactivity, is thought to be associated with susceptibility to Rheumatic Fever. We have demonstrated that a sustained antibody response to the group A streptococcal carbohydrate antigen is peculiar to a subgroup of rheumatic fever patients with persistent valvular heart disease. The clinical manifestations and exaggerated immune responsivenses in rheumatic fever is analogous to other rheumatic/collagen vascular disease in which HLA-linked immune dysfunction and altered immunoregulation have been demonstrated (i.e., systemic lupus, Sjogrens Syndrome). Rheumatic fever patients may present therefore, a unique opportunity to study the relationship between hyper-responsiveness to a specific antigen and the HLA-D system. To investigate this relationship, we will study the in vitro production of antibody to streptococcal and non-streptococcal antigens by mononuclear leukocytes of patients with rheumatic fever and non-rheumatic controls. This study group will include 60 patients with rheumatic fever, with or without cardiac involvement, and an equal number of siblings of these patients. The age-matched controls will include normal individuals, patients with uncomplicated streptococcal infections and patients with post-streptococcal nephritis. The results of the in vitor antibody production will be correlated with the HLA type, with the serum antibody to the group A streptococcal carbohydrate, and with cardiac involvement. In addition to providing a model for a relationship between HLA-linked immune responsiveness to a defined antigen in man, the data will further substantiate the role of an immune in the patheogenesis or rheumatic fever. The process by which a streptococcal infection and the altered immunoregulation lead to rheumatic fever will be subsequently investigated. The data may also provide a method for identifying susceptibility to rheumatic fever. This study represents a multidisciplinary endeavor involving the Departments of pediatrics, lmmunology and Pathology.